Abstract
Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine‐sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1‐R exhibiting a 20‐fold IC~50~‐value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti‐oxidants, in the KLM1‐R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine‐induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine‐induced ROS levels. Furthermore interferon‐γ suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1‐R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine. © 2004 Wiley‐Liss, Inc.